Reatividade vascular em ratos normotensos e hipertensos (modelo Renoclip) com diferentes fenótipos da enzima conversora de angiotensina I (ECA) plasmática

• Ano de defesa: 2016
• Autor(a) principal: Dias, Alyne Stella do Espirito Santo Pisano [UNIFESP]
• Orientador(a): Landman, Maria Teresa Riggio de Lima [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/48912/00130000289rt
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Angiotensina; Hipertensão; Eca; Fenótipo; Receptor
• Palavras-chave em Inglês: Angiotensin; Hypertension; Eca; Phenotype; Receptor
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3740769; http://repositorio.unifesp.br/handle/11600/46226

The outbred of Wistar rats with ECA plasmatic activity high (ECAa) and low (ECAb) originated the lineages Wistar INFAR/ECAa and Wistar INFAR/ECAb. Despite the phenotypic difference, these lineages are normotensive. The ECAb rats showed to be more sensitive to: 1) captopril (CAP) treatment and to in vitro administration of Ang I and Ang II to aortic rings, in the presence and absence of its inhibitor or antagonist, indicating that this sensitivity is at the AT1 receptor level; 2) the induction of hypertension by the DOCA-sal model associated with nephrectomy; but 3) they do not show hypertension reversal over time. The purpose of this project was to study the compensatory mechanisms that could be involved in the observed dissociation between ECA plasmatic activity and blood pressure (PA) responses by correlating pressure levels to the efficacy of drugs that act in PA regulation, by evaluating the vascular reactivity by : 1) the direct measurement of PA in carotid artery of normotensive ECA rats and 2) the indirect methodology of PA evaluation, by the tail method, in hypertensive animals by the Goldblatt model. The evaluation of AT1 receptors, by measurement of calcium mobilization, and its quantification by Western-blotting were also performed during this present work. The induction of the renovascular hypertension was performed as described by Bergamaschi et al, 1996 following the Goldblatt model (1934). The evaluation of intracellular calcium mobilization was performed in smooth muscle cultured cells of aortic thoracic artery, by fluorescence and the AT1 quantification, in heart samples, by the Western¬blot method. ECAa and ECAb rats had the same pattern during the induction of hypertension showing the same delta of pressor response, about 100 mm Hg, after six weeks of surgery. After CAP treatment, ECAb hypertensive rats, showed to be more sensitive to the lower doses of CAP than ECAa rats. The plasmatic ACE activity in the renovascular model of hypertension increased in both ECAa and ECAb rats, in the same manner, and was not affected by CAP treatment. After 3 weeks of washout period, the ECAb animals showed an apparent left ventricular hypertrophy (HVE), not observed in ECAa rats. Based in these results, we quantified AT1 receptors in heart samples of ECAa and ECAb normotensive rats and no difference was found in this parameter. In PA direct measurement, in vivo, these distinct phenotypic rats showed to have similar responses to autonomic nervous system (SNA) stimulation, indicating that this system is not affected by the enzymatic phenotype. PA, Ang I and Ang II responses in ECAb rats were more sensitive than in ECAa rats, indicating, again, a discrepancy at the AT1 receptor level or after its activation. Based on these results, we evaluate the intracellular calcium mobilization in animals with different ECA plasmatic activity and ECAb rats showed to mobilize more calcium than ECAa rats, at 10¬5 M concentration. With losartan blockade, ECAb rats showed a concentration-dependent response by Ang II stimulation, not observed in ECAa rats. Desensitization, internalization, density or conformational changes at the AT1 receptors could be involved in this different sensitivity in ECAb rats.